Abstract
BackgroundZASC1 is a zinc finger-containing transcription factor that was previously shown to bind to specific DNA binding sites in the Moloney murine leukemia virus (Mo-MuLV) promoter and is required for efficient viral mRNA transcription (J. Virol. 84:7473-7483, 2010).MethodsTo determine whether this cellular factor influences Mo-MuLV replication and viral disease pathogenesis in vivo, we generated a ZASC1 knockout mouse model and completed both early infection and long term disease pathogenesis studies.ResultsMice lacking ZASC1 were born at the expected Mendelian ratio and showed no obvious physical or behavioral defects. Analysis of bone marrow samples revealed a specific increase in a common myeloid progenitor cell population in ZASC1-deficient mice, a result that is of considerable interest because osteoclasts derived from the myeloid lineage are among the first bone marrow cells infected by Mo-MuLV (J. Virol. 73: 1617-1623, 1999). Indeed, Mo-MuLV infection of neonatal mice revealed that ZASC1 is required for efficient early virus replication in the bone marrow, but not in the thymus or spleen. However, the absence of ZASC1 did not influence the timing of subsequent tumor progression or the types of tumors resulting from virus infection.ConclusionsThese studies have revealed that ZASC1 is important for myeloid cell differentiation in the bone marrow compartment and that this cellular factor is required for efficient Mo-MuLV replication in this tissue at an early time point post-infection.
Highlights
ZASC1 is a zinc finger-containing transcription factor that was previously shown to bind to specific DNA binding sites in the Moloney murine leukemia virus (Mo-MuLV) promoter and is required for efficient viral mRNA transcription
Our groups employed a forward genetic screen that identified ZASC1 (Zinc Finger Amplified in Esophageal Squamous Carcinoma 1 or ZNF639) as a cellular transcription factor that binds three specific DNA sequences located within the unique 3′ (U3) region of the Mo-MuLV genome [8]
We found that hematopoietic stem cells (HSCs) and multipotent progenitors (MPPs) populations were comparable between ZASC1−/− and ZASC1+/+ mice, but there was a statistically significant 1.5-fold increase (p-value = 0.012) in the heterogenous lin-ska-kit+ (LK) compartment in all ZASC1-deficient animals tested (Figure 3A and 3B)
Summary
ZASC1 is a zinc finger-containing transcription factor that was previously shown to bind to specific DNA binding sites in the Moloney murine leukemia virus (Mo-MuLV) promoter and is required for efficient viral mRNA transcription Transcription of retroviral genomes involves numerous cellular transcription factors that bind to the unique 3′ (U3) enhancer element located in the viral promoter [1,2,3,4]. Our groups employed a forward genetic screen that identified ZASC1 (Zinc Finger Amplified in Esophageal Squamous Carcinoma 1 or ZNF639) as a cellular transcription factor that binds three specific DNA sequences located within the U3 region of the Mo-MuLV genome [8]. More recently we have found that ZASC1 is required for efficient HIV-1 gene expression by a mechanism that is associated with recruitment of a viral Tat/cellular pTEFb complex to the viral core promoter (Bruce et al in preparation)
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